Vai ai contenuti. | Spostati sulla navigazione | Spostati sulla ricerca | Vai al menu | Contatti | Accessibilità

| Crea un account

Guarise, Cristian (2008) Sintesi su fase solida, valutazione catalitica e di riconoscimento molecolare di sistemi tripodali. [Tesi di dottorato]

Full text disponibile come:

[img]
Anteprima
Documento PDF
1915Kb

Abstract (inglese)

Solid phase synthesis of tripodal systems and study of their catalytic and molecular recognitions properties

Tripodal molecular structures are increasingly applied in the fields of catalysis, recognition, sensing, and biomimetics. The problem is that the combinatorial approach, that gives access to large amounts of heterofunctionalized receptors, uses orthogonally protected scaffolds and requires a very laborious synthesis. In this research project, a versatile synthetic approach for the functionalization of tripodal scaffold molecules on solid support, was developed. The generality of this approach was illustrated by the functionalization of three structurally diverse A3-type scaffold molecules containing multiple amino-groups (1a, 1,3,5-tris(aminoethyl)-2,4,6-triethylbenzene; 1b, tris(2-aminoethyl)amine; 1c, triazacyclononane) with a variety of different functional groups. Advantages of this approach are its simplicity and the freedom to functionalise any desirable scaffold molecule, without the use of protecting groups or special functionalisation patterns (for instance AB3). Intrinsic problems related to the attachment of tripodal scaffolds to a resin (for example mono- versus polyadducts and intramolecular cyclizations) were studied and solutions were provided. Importantly, protecting groups on the scaffold molecule were never used, which significantly facilitates scaffold variation, for instance for combinatorial studies.
The synthetic approach was used in order to obtain multivalent C3-symmetrical molecules as artificial models of enzymes catalytic site. The general goal was to understand whether the scaffold structure influenced the cooperativity between the functional groups.
First, we have synthesized an artificial model of a serine protease (or esterase), by connecting to scaffold 1a different combinations of peptides, based on the amino acids of the active site of the proteolytic enzyme: Asp, His and Ser. Studies of these compounds in the hydrolysis of activated esters revealed catalytic activity for the scaffold 1a functionalized with the active sequence -CO-Asp-His-H.
Subsequently, we have functionalized a Calix[4]arene scaffold with the same active sequence for which a significant 86-fold rate enhancement compared to that of the uncatalyzed background reaction has been observed. This study showed cooperativity between the functional groups only in the hydrolysis reactions performed with excess of catalyst, likely because the catalyst does not provide a well defined active site. Second, a tripodal scaffold functionalized with the -CO-Asp-Pro-Pro-H sequence, active in aldol asymmetric condensations, has been studied. Catalytic studies, performed with excess of catalyst, show that also for this catalyst the presence of the scaffold does not result in an increase in the enantioselectivity with respect to the monomeric unit. In these tripodal catalysts show a prevailing divergent structure that does not allow high cooperativity between the functional groups. Consequently we shifted our attention to tripodals structures for application in the field of molecular (bio)recognition.
For this purpose, we have chosen to study multivalent HIV-1 fusion inhibitors based on small 310-helical foldamers.
HIV-1 entry into target cells is a multistep process involving a series of proteins and cofactors. Glycoproteins gp41, decorating in the surface of HIV-1 play key roles in this process. The ectodomain (extraviral) of gp41 consists of three important regions: an N-terminal fusion sequence that inserts into the target cell membrane, and two helical regions containing two hydrophobic heptad repeat units (denoted as the N- and C-helical regions, respectively). The N-HR regions of three gp41 molecules form a trimeric ?-helical coiled-coil. Upon dissociation of gp120 from the complex, a six-helix bundle forms, in which the C-helical regions wrap around the inner coil in an antiparallel fashion. We have studied a series of strategies for the synthesis of small peptide inhibitors, based on small 310-helical foldamers. These molecules have been designed for the inhibition of HIV-1 replication by binding to the inner trimeric coiled coil, thus preventing the formation of the six-helix bundle, which is essential for the complete fusion of the virus to target cell membranes.
The 310-helix conformation is induced with the introduction of 5 Aib-residues in the peptide inhibitor sequence. In that way the amino acids Trp, Trp, and Ile (the WWI epitope) of the peptide are placed in the same positions of the N-HR helix regions of gp41 molecules. Currently we are studying a synthetic strategy in order to covalently link this foldamer to a tripodal scaffold (with oligoPEG spacers).


Statistiche Download - Aggiungi a RefWorks
Tipo di EPrint:Tesi di dottorato
Relatore:Scrimin, Paolo M.
Correlatore:Prins, Leonard
Dottorato (corsi e scuole):Ciclo 20 > Scuole per il 20simo ciclo > SCIENZE MOLECOLARI > SCIENZE CHIMICHE
Data di deposito della tesi:31 Gennaio 2008
Anno di Pubblicazione:31 Gennaio 2008
Parole chiave (italiano / inglese):sistemi tripodali catalisi esterasi aldolasi inibitore HIV sintesi su fase solida
Settori scientifico-disciplinari MIUR:Area 03 - Scienze chimiche > CHIM/06 Chimica organica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Chimiche
Codice ID:403
Depositato il:10 Ott 2008
Simple Metadata
Full Metadata
EndNote Format

Bibliografia

I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

1. Per review: (a) Zhou, J.; Tang, Y. Chem.Soc.Rev. 2005, 34, 664. (b) Moberg, C. Angew.Chem.Int.Ed. 1998, 37, 248. (c) Berreau, L.M. Eur.J.Inorg.Chem. 2006, 273. Cerca con Google

2. Per review: (a) Gibson, S.E.; Castaldi, M.P. Chem.Commun. 2006, 3045. (b) Moberg, C. Angew.Chem.Int.Ed. 2006, 45, 4721. (c) Yoon, J.; Kim, S.K.; Singh, N.J., Kim, K.S. Chem.Soc.Rev. 2006, 35, 355. (c) Singh, Y.; Dolphin, G.T.; Razkin, J.; Dumy, P. ChemBioChem 2006, 7, 1298. Cerca con Google

3. Per review: (a) Kuswandi, B.; Nuriman; Verboom, W.; Reinhoudt, D.N. Sensors, 2006, 6, 978. (b) Nguyen, B.T.; Anslyn, E.V. Coord.Chem.Rev. 2006, 250, 3118. (c) Wiskur, S. L.; Ait-Haddou, H.; Lavigne, J.J.;Anslyn E.V. Acc. Chem. Res., 2001, 34, 963. (d) Wright, A. T.; Anslyn, E.V. Chem.Soc.Rev. 2006, 35, 14. Cerca con Google

4. Per review: (a) Gibson, S.E.; Castaldi, M.P. Angew.Chem.Int.Ed. 2006, 45, 4718. (b) Parkin, G. Chem.Commun. 2000, 1971. Cerca con Google

5. Vacca, A.; Nativi, C.; Cacciarini, M.; Pergoli, R.; Roelens, S. J.Am.Chem.Soc. 2004, 126, 16456. Cerca con Google

6. Kim, S. G.; Kim, K. H.; Kim, Y. K.; Shin, S. K.; Ahn, K.H. J. Am. Chem. Soc., 2003, 125, 13819 Cerca con Google

7. Schneider, S.E.; O’Neil S.N.;Anslyn E.V. J.Am.Chem.Soc. 2000, 122, 542. Cerca con Google

8. Wright, A. T.; Zhong Z.; Anslyn, E. V. Angew. Chem., 1999,117, 5825. (b) Wright, A. T.; Zhong Z.; Anslyn, E. V. Angew. Chem. Int. Ed., 1999, 44, 5679. Cerca con Google

9. McCleskey, S. C.; Griffin, M. J.; Schneider, S. E.; McDevitt, J. T.; Anslyn, E. V. J. Am. Chem. Soc. 2003, 125, 1114. Cerca con Google

10. Wright, A. T.; Griffin, M. J.; Zhong, Z.; McCleskey, S. C.; Anslyn E. V.; McDevitt, J. T. Angew. Chem., Int. Ed., 2005, 44, 6375. Cerca con Google

11. Tobey, S. L.; Anslyn E. V. Org. Lett., 2003, 5, 2029. Cerca con Google

12. Kwak, J.; Capua, A, D.; Locardi, E.; Goodman, M. J. Am. Chem. Soc. 2002, 124, 14085. Cerca con Google

13. Tam, J.P.; Yu, Qitao. Org. Lett., 2002, 4, 4167. Cerca con Google

14. Fournel, S.; Wieckowski, S.; Sun, W.; Trouche, N.; Dumortier, H.; Bianco, A.; Chaloin, O.; Habib, M.; Peter, J.C.; Schneider, P.; Vray, B.; Toes, R.T.; Offringa, R.; Melief, C.J.M.; Hoebeke, J.; Guichard, G. Nature Chem. Biol., 2005, 1, 377. (b) Trouche, N.; Wieckowski, S.; Sun,W.; Chaloin, O.; Hoebeke, J.; Fournel, S. Guichard, G. J. Am. Chem. Soc. 2007, 129, 13480. Cerca con Google

15. Lin, H.; Fischbach, M. A.; Gatto, G. J.; Liu, D. R.; Walsh, C. T. J. Am. Chem. Soc. 2006, 128, 9324. Cerca con Google

16. Boturyn, D.; Coll, J.-L-; Garanger, E.; Favrot, M.-C.; Dumy, P. J.Am.Chem.Soc. 2004, 126, 5730. Cerca con Google

17. Mba, M.; Prins, L. J.; Licini, G. Org. Lett., 2007, 9, 21. Cerca con Google

18. Molenveld, P.; Stikvoort, W.M.G.; Kooijman, H.; Spek, A.L.; Engbersen, J.F.J.; Reinhoudt, D.N. J.Org.Chem. 1999, 64, 3896. Cerca con Google

19. Cacciapaglia, R.; Casnati, A.; Mandolini, L.; Seracchi, A.; Reinhoudt, D.T.; Salvio, R.; Sartori, A.; Ungano, R. J. Am. Chem. Soc. 2007, 129, 12512. Cerca con Google

20. Komiyama, M.; Kina, S.; Matsumura, K.; Sumaoka, J.; Tobey, S.; Lynch, V. M.; Anslyn, R. J. Am. Chem. Soc. 2002, 124, 13731. Cerca con Google

21. Scarso, A.; Scheffer, U.; Gobel, M.; Broxterman, Q.B.; Kaptein, B.; Formaggio, F.; Toniolo, C.; Scrimin, P. Proc. Nat. Accad. Sci. Usa, 2002, 99, 5144. (b) Scarso, A.; Zaupa, G.; Houillon, F.B.; Prins, L.J.; Scrimin, P. J.Org.Chem. 2007, 72, 376. Cerca con Google

22. Rao, J.; Lahiri, J.; Isaacs, L.; Weis, R.M.; Whitesides, G.M. Science, 1998, 280, 708. Cerca con Google

23. Badjic, J.D.; Balzani, V.; Credi, A.; Silvi, S.; Stoddart, J.F. Science, 2004, 303, 1845. Cerca con Google

24. Lata, S.;Reichel, A.; Brock, R.; Tampe’´, R.; Piehler, J. J. Am. Chem. Soc. 2005, 127, 10205. Cerca con Google

25. Posner, R. G.; Geng, D.; Haymore, S.; Bogert, J.; Pecht, I.; Licht, A.; Savage, P. B. Org. Lett., 2007, 9, 3551. Cerca con Google

26. Zaupa, G.; Martin, M.; Prins, L.J.; Scrimin, P. New.J.Chem. 2006, 30, 1493. Cerca con Google

27. Opatz, T.; Liskamp, R.J.M. J.Comb.Chem. 2002, 4, 275-284. (b) Chamorro, C.; Hofman, J.-W.; Liskamp, R.J.M. Tetrahedron, 2004, 60, 8691. Cerca con Google

28. Dumy, P.; Eggleston, I.M.; Cervigni, S.; Sila, U.; Sun, X.; Mutter, M. Tet.Lett. 1995, 36, 1255. (b) Zhou, X.-T.; Rehman, A.; Li, C.; Savage, P.B. Org.Lett. 2000, 2, 3015. (c) Virta, P.; Karskela, M.; Lönnberg, H. J.Org.Chem. 2006, 71, 1989-1999. Cerca con Google

29. Li, S.; Marthandan, N.;Bowerman, D.; Garner, H.R.; Kodadek, T. Chem. Commun. 2005, 581. Cerca con Google

30. Guarise, C.; Prins, L.J.; Scrimin, P. Tetrahedron, 2006, 62, 11670. Cerca con Google

31. Mink, D.; Mecozzi, S.; Rebek, J., Jr. Tet. Lett. 1998, 39, 5709. (b) Rasmussen, P.H.; Rebek, J., Jr. Tet. Lett. 1999, 40, 3511. (c) Bowen, T.; Planalp, R.P.; Brechbiel, M.W. Bioorg.Med.Chem.Lett. 1996, 6, 807. (d) Hennrich, G.; Anslyn, E.V. Chem.Eur.J. 2002, 8, 2219. Cerca con Google

32. Schneider, S.E.; O'Neill, S.N.; Anslyn, E.V. J.Am.Chem.Soc. 2000, 122, 542. Cerca con Google

33. Ashraf, M.A.; Notta, J.K.; Snaith, J.S. Tet. Lett. 2003, 44, 9115. Cerca con Google

34. Guarise, C.; Prins, L.J.; Scrimin, P. Tetrahedron, 2006, 62, 11670. Cerca con Google

35. Guarise, C.; Zaupa, G.; Prins, L.J.; Scrimin, P. J.Org.Chem. 2008, Submitted manuscript. Cerca con Google

36. Schneider, S.E.; O'Neill, S.N.; Anslyn, E.V. J.Am.Chem.Soc. 2000, 122, 542. (b)Hennrich, G.; Anslyn, E.V. Chem.Eur.J. 2002, 8, 2219 Cerca con Google

37. Cacciapaglia, R.; Di Stefano S.; Mandolini, L. Acc. Chem. Res. 2004, 37, 113. (b) Mandolini, L. Adv. Phys. Org. Chem. 1986, 22, 1. Cerca con Google

38. Letsinger, R.L.; Kornet, M.J. J. Am. Chem. Soc. 1963, 85, 3045. (b) Felix, A. M.; Merrifield, R.B. J. Am. Chem. Soc. 1970, 92, 1385. (c) Matsueda, R.; Maruyama, H.; Kitazawa, E.; Takahagi, H.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1973, 46, 3240. (d) Henkel, B.; Zhang, L.; Bayer, E. Liebigs Ann. Recl. 1997, 2161. (e) Léger, R.; Yen, R.; She, M.W.; Lee, V.J.; Hecker, S.J. Tetrahedron Lett. 1998, 39, 4171. (f) Thieriet, N.; Guibé, F.; Albericio, F. Org. Lett. 2000, 2, 1815. (g) Brase, S.; Kirchhoff, J.H.; Kobberling, J. Tetrahedron 2003, 59, 885. Cerca con Google

39. Ashraf, M.A.; Notta, J.K.; Snaith, J.S. Tet.Lett. 2003, 44, 9115-9119. Cerca con Google

40. Akaji, K.; Kiso, Y.; Carpino, L.A. J.Chem.Soc., Chem. Commun. 1990, 584. (b) Kochansky, J.; Wagner, R.M. Tetrahedron Lett. 1992, 33, 8007. Cerca con Google

41. Akaji, K.; Tanaka, H.; Itoh, H.; Imai, J.; Fujiwara, Y.; Kimura, T.; Kiso, Y. Chem. Pharm. Bull. 1990, 38, 3471. Cerca con Google

42. Per review: (a) Zhou, J.; Tang, Y. Chem.Soc.Rev. 2005, 34, 664. (b) Moberg, C. Angew.Chem.Int.Ed. 1998, 37, 248. (c) Berreau, L.M. Eur.J.Inorg.Chem. 2006, 273. Cerca con Google

43. Per review: (a) Gibson, S.E.; Castaldi, M.P. Chem.Commun. 2006, 3045. (b) Moberg, C. Angew.Chem.Int.Ed. 2006, 45, 4721. (c) Yoon, J.; Kim, S.K.; Singh, N.J., Kim, K.S. Chem.Soc.Rev. 2006, 35, 355. (c) Singh, Y.; Dolphin, G.T.; Razkin, J.; Dumy, P. ChemBioChem 2006, 7, 1298. Cerca con Google

44. Ding, X.C.; Rasmussen, B.F.; Petsko, G.A.; Ringe, D. Biochemistry 1994, 33, 9285. Cerca con Google

45. Lagnoux, D.; Delort, E.; Douat-Casassus, C.; Esposito, A.; Reymond, J.L. Chem. Eur. J. 2004, 10, 1215. Cerca con Google

46. Delort, E.; Darbre, T.; Reymond, J.L. J.Am.Chem.Soc. 2004, 126, 15842. Cerca con Google

47. Guler, M.O.; Stupp, S.I. J.Am.Chem.Soc. 2007, 129, 12082. Cerca con Google

48. Guarise, C.; Prins, L.J.; Scrimin, P. Tetrahedron, 2006, 62, 11670. (b) Guarise, C.; Zaupa, G.; Prins, L.J.; Scrimin, P. J.Org.Chem. 2008, Submitted manuscript. Cerca con Google

49. Hennrich, G.; Anslyn, E.V. Chem. Eur. J. 2002, 8, 2218. Cerca con Google

50. Guarise, C.; Manea, F.; Zaupa, G.; PAsquato, L.; Prins, L.J.; Scrimin, P. J. of Pept. Sci., 2008, In press manuscript. Cerca con Google

51. Baldini, L.; Casnati, A.; Sansone, F.; Ungaro, R. Chem. Soc. Rev. 2007, 36, 254. Cerca con Google

52. List, B.; Lerner, R. A.; Barbas III, C.F. J.Am.Chem.Soc. 2000, 122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. J.Am.Chem.Soc. 2001, 123, 5260. (c) Krattiger, P.; Kovasky, R.; Revel, J.D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7, 1101. (d) Kofoed, J.; Darbre, T.; Reymond, J.L. Org. Biomol. Chem. 2006, 4, 3268. (e) Revell, J.D.; Wennemers, H. Tetrahedron 2007, 63, 8420. Cerca con Google

53. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920. Cerca con Google

54. Chan, D.C.; Kim, P.S. Cell. 1998, 93, 681.(b) Zwick, M.B.; Saphire, E.O.; Burton, D.R. Nature Med. 2004, 10, 133.(c) Markosyan, R.M.; Ma, X.; Cohen, F.S.; Melikyan, G.B. Virology 2002, 302, 174. (d) Gallo, S.A.; Finnegan, C.M.; Viard, M.; Raviv, Y.; Dimitrov, A.; Rawat, S.S.; Puri, A.; Durell, S.; Blumenthal, R. Biochim.Biophys.Acta-Biomembranes 2003, 1614, 36. Cerca con Google

55. Melikyan, G.B.; Markosyan, R.M.; Hemmati, H.; Delmedico, M.K.; Lambert, D.M.; Cohen, F.S. J.Chem.Biol. 2000, 151, 413. Cerca con Google

56. Pöhlmann, S.; Reeves, J.D. Curr.Pharm.Design 2006, 12, 1963. (b) Krambovitis, E.; Porichis, F.; Spandidos, D.A. Act.Pharm.Sin. 2005, 1165. Cerca con Google

57. Manfredi, R.; Sabbatani, S. Curr.Med.Chem. 2006, 13, 2369. Cerca con Google

58. Chan, D.C.; Chutkowski, C.T.; Kim, P.S. Proc. Natl. Acad. Sci. USA 1998, 95, 15613. Sia, S.K.; Kim, P.S. Proc. Natl. Acad. Sci. USA 2003, 100, 9756. Cerca con Google

59. Eckert, D.M.; Malashkevich, V.N.; Hong, L.H.; Carr, P.A.; Kim, P.S. Cell 1999, 99, 103. (b) Sia, S.K.; Carr, P.A.; Cochran, A.G.; Malashkevich, V.N.; Kim, P.S. Proc.Natl.Acad.Sci. 2002, 99, 14664. Cerca con Google

60. Stephens, O.M.; Kim, S.; Welch, B.D.; Hodsdon, M.E.; Kay, M.S.; Schepartz, J.Am.Chem.Soc. 2005, 127, 13126. Cerca con Google

61. Ernst, J.T.; Kutzki, O.; Debnath, A.K.; Jiang, S.; Lu, H.; Hamilton, A.D. Angew.Chem.Int.Ed. 2002, 41, 278. Cerca con Google

62. Ferrer, M.; Kapoor, T.M.; Strassmaier, T.; Weissenhorn, W.; Skehel, J.J.; Oprian, D.; Schreiber, S.L.; Wiley, D.C.; Harrison, S.C. Nature Struct.Biol. 1999 6, 953. Cerca con Google

63. Weissenhorn, W.; Desson, A.; Harrison, S.C.; Skehel, J.J.; Wiley, D.C. Nature 1997, 387, 426. Chan, D.C.; Fass, D.; Berger, J.M.; Kim, P.S. Cell, Cerca con Google

64. Karle, I.L.; Balarams, P. Biochem. 1990, 29, 6747 (b) Haynes, S.R.; Hagius S. D.; Juban, M.M.; Elzer, P.H.;Hammer, R.P. J. Peptide Res. 2005, 66, 333. Bellanda, Mammi, (c) Pengo, P.; Pasquato, L.; Moro, S.; Brigo, A.; Focolari, F.; Broxterman, O.B.; Kaptein, B.; Scrimin, P. Angew.Chem.Int.Ed. 2003, 42, 3388 (d) S.; Geremia, S.; Demitri, N.; Randaccio, L.; Broxterman, Q.B.; Kaptein, B.; Pengo, P.; Pasquato, L.; Scrimin, P. Chem. Eur. J. 2007, 13, 407. Cerca con Google

65. Yang, Y.; Sweeney, W.V.; Schneider, K.; Thörnqvist, S.; Chait, B.T.; and Tam, J.P. Tet.Lett. 1994, 35, 9689. Cerca con Google

66. Guarise, C.; Prins, L.J.; Scrimin, P. Tetrahedron, 2006, 62, 11670. (b) Guarise, C.; Zaupa, G.; Prins, L.J.; Scrimin, P. J.Org.Chem. 2008, Submitted manuscript. Cerca con Google

67. Samuel, K. S.; Peter, A. C.; Andrea, G.C.; Vladimir N.M.; Peter, S. K. PNAS, 2002, 23, 14664. Cerca con Google

68. Debra, M. E.; Peter S.K. PNAS, 2001, 98, 11187. Cerca con Google

Download statistics

Solo per lo Staff dell Archivio: Modifica questo record